Spheres of Influence: Insights into Salmonella Pathogenesis from Intestinal Organoids

Abstract

The molecular complexity of host-pathogen interactions remains poorly understood in many infectious diseases, particularly in humans due to the limited availability of reliable and specific experimental models. To bridge the gap between classical two-dimensional culture systems, which often involve transformed cell lines that may not have all the physiologic properties of primary cells, and in vivo animal studies, researchers have developed the organoid model system. Organoids are complex three-dimensional structures that are generated in vitro from primary cells and can recapitulate key in vivo properties of an organ such as structural organization, multicellularity, and function. In this review, we discuss how organoids have been deployed in exploring Salmonella infection in mice and humans. In addition, we summarize the recent advancements that hold promise to elevate our understanding of the interactions and crosstalk between multiple cell types and the microbiota with Salmonella. These models have the potential for improving clinical outcomes and future prophylactic and therapeutic intervention strategies.

Stem cell‐derived enteroid cultures as a tool for dissecting host‐parasite interactions in the small intestinal epithelium

“…Viral studies using the enteroid model include rotavirus, enteric adenovirus and norovirus 126‐130 . Bacterial studies using intestinal organoids include E coli , Salmonella , Vibrio cholerae , Shigella flexneri and Clostridium difficile 8,131‐138 . The use of the intestinal organoid model has also been concentrated on drug development assays and cancer models 139,140‐142 …”

A versatile human intestinal organoid-derived epithelial monolayer model for the study of enteric pathogens

“…The use of human-derived intestinal organoids to study bacterial pathogenesis has recently increased (39)(40)(41)(42). Prior to this advancement, most enteric pathogenesis studies were limited to immortalized cell lines and/or animal models.…”

“…Organoid-derived epithelial monolayer models like the HIODEM have enabled infection analyses by providing a process by which pathogens can directly interact with the apical side of the epithelium (11,24,33,(54)(55)(56)(57)(58). While three-dimensional organoid systems are available (40,(59)(60)(61)(62)(63) and "apical-out" organoid systems have been developed 64 ileum, cecum, or colon, despite the overall pluripotent state of the stem cells (11,15,71).…”

“…Organoid-derived epithelial monolayer models like the HIODEM have enabled infection analyses by providing a process by which pathogens can directly interact with the apical side of the epithelium (11, 24, 33, 54-58). While three-dimensional organoid systems are available (40, 59-63) and “apical-out” organoid systems have been developed (64), HIODEM and other 2-D systems offer easily accessible monolayers for pathogenesis studies in which apical and basolateral cytokine secretion profiles and changes in TEER can be examined in a standard transwell culture setting. Similar to traditional polarized models with Caco-2 and T84 cells (65-67), the polarized monolayer of HIODEM allows for a robust infection without need of centrifuging bacteria onto the cells, which is a common practice for infection analyses performed with standard, nonpolarized cell lines (68-70).…”

Special Issue “Salmonella: Pathogenesis and Host Restriction”

“…Following invasion, Salmonella will spread via the bloodstream to the spleen, liver, and gallbladder, where they replicate in macrophages. Verma et al [ 10 ] have reviewed the use of organoids as a complex model to study Salmonella host cell interactions. Each step of the infection process needs to be tightly regulated.…”